Text 2: Prenatal origins of heart disease

Heart disease is the greatest killer in the developed world today, currently accounting for 30% of all deaths in Australia. A concept which is familiar to us all is that traditional risk factors such as smoking, obesity, and genetic make-up increase the risk of heart disease. However, it is now becoming apparent that another factor is at play – a developmental programming that is predetermined before birth, not only by our genes but also by their interaction with the quality of our prenatal environment.

Pregnancies that are complicated by sub-optimal conditions in the womb, such as happens during pre-eclampsia or placental insufficiency, enforce physiological adaptations in the unborn child and placenta. While these adaptations are necessary to maintain viable pregnancy and sustain life before birth, they come at a cost. The biological trade-off is reduced growth, which may in turn affect the development of key organs and systems such as the heart and circulation, thereby increasing the risk of cardiovascular disease in adult life. Overwhelming evidence in more than a dozen countries has linked development under adverse intrauterine conditions leading to low birth weight with increased rates in adulthood of coronary heart disease and its major risk factors – hypertension, atherosclerosis and diabetes.

The idea that a foetus’s susceptibility to disease in later life could be programmed by the conditions in the womb has been taken up vigorously by the international research community, with considerable efforts concentrating on nutrient supply across the placenta as a risk factor. But that is just part of the story: how much oxygen is available to the foetus is also a determinant of growth and of the risk of adult disease. Dr Dino Giussani’s research group at Cambridge University in the UK is asking what effect reduced oxygen has on foetal development by studying populations at high altitude.

Giussani’s team studied birth weight records from healthy term pregnancies in two Bolivian cities at obstetric hospitals and clinics selectively attended by women from either high-income or low-income backgrounds. Bolivia lies at the heart of South America, split by the Andean Cordillera into areas of very high altitude to the west and areas at sea-level to the east, as the country extends into the Amazon Basin. At 400m and almost 4000m above sea-level, respectively, the Bolivian cities of Santa Cruz and La Paz are striking examples of this difference. Pregnancies at high altitude are subjected to a lower partial pressure of oxygen in the atmosphere compared with those at sea-level. Women living at high altitude in La Paz are more likely to give birth to underweight babies than women living in Santa Cruz. But is this a result of reduced oxygen in the womb or poorer nutritional status?

What Giussani found was that the high-altitude babies showed a pronounced reduction in birth weight compared with low-altitude babies, even in cases of high maternal nutritional status. Babies born to low-income mothers at sea-level also showed a reduction in birth weight, but the effect of under-nutrition was not as pronounced as the effect of high altitude on birth weight; clearly, foetal oxygenation was a more important determinant of foetal growth within these communities. Remarkably, although one might assume that babies born to mothers of low socio-economic status at high altitude would show the greatest reduction in birth weight, these babies were actually heavier than babies born to high-income mothers at high altitude. It turns out that the difference lies in ancestry.

The lower socio-economic groups of La Paz are almost entirely made up of Aymara Indians, an ancient ethnic group with a history in the Bolivian highlands spanning a couple of millennia. On the other hand, individuals of higher socio-economic status represent a largely European and North American admixture, relative newcomers to high altitude. It seems therefore that an ancestry linked to prolonged high-altitude residence confers protection against reduced atmospheric oxygen.

Giussani’s group also discovered that they can replicate the findings observed in Andean pregnancies in hen eggs: fertilised eggs from Bolivian birds native to sea-level show growth restriction when incubated at high altitude, whereas eggs from birds that are native to high altitude show a smaller growth restriction. Moving fertilised eggs from hens native to high altitude down to sea-level not only restored growth, but the embryos were actually larger than sea-level embryos incubated at sea-level. The researchers could thereby demonstrate something that only generations of migration in human populations would reveal. What’s more, when looking for early markers of cardiovascular disease, the researchers discovered that growth restriction at high altitude was indeed linked with cardiovascular defects – shown by an increase in the thickness of the walls of the chick heart and aorta. This all suggests the possibility of halting the development of heart disease at its very origin, bringing preventive medicine back into the womb.